Thrombin plays an important role in the coagulation process, where it as last enzyme, in the coagulation cascade, transfer fibrinogen to polymerizable fibrin. This is done by splitting of Arg-bonds. Thrombin has just close to its active center a "specificity pocket" with great affinity for the positively charged guanidion group in Arg. This knowledge has been used for construction of synthetic substrates and inhibitors of thrombin. Since a long time it is known that substituted Arg esters can be split by thrombin, e.g. Bz-Arg-OEt (BAEE) and Tos-Arg-OMe (TAME). The last-named ester acts, by being a competitive substrate, also as inhibitor to the reaction of thrombin with fibrinogen. The plasma coagulation time is prolonged e.g. by addition of TAME.
A better thrombin inhibitor can be obtained by making the Arg-bond not cleavable. Okamoto.sup.(1,2) has described thrombin inhibitors, where the carboxylic group of Arg is bound to sec amines: ##STR5## Markwardt.sup.(3,4) has modified the structure II by inserting the synthetic amino acid p-amidinophenylalanine (Aph), an analog to Arg, instead of Arg. The compounds (III) thereby obtained seem to be about as good thrombin inhibitors as the corresponding compounds (II) made by Okamoto. ##STR6##
Another arginine anolog, p-guanidinophenylalanine (Gph), was first synthezised by Elliot.sup.(5). Klausner.sup.(6) synthesized the derivative Tos-Gph-OMe, which appeared to be a good substrate for trypsin, but on the other hand a bad substrate for thrombin but with ability to inhibit the amidase- and esterase activity of thrombin. Tsunematso.sup.(7) has synthesized Bz-Gph-OEt too and has found that it as substrate for trypsin is comparable with Tos-Gph-OMe and Tos-Arg-OMe (TAME).